CN114126703A

CN114126703A - Neuromodulation energy application techniques

Info

Publication number: CN114126703A
Application number: CN202080050384.1A
Authority: CN
Inventors: 克里斯托弗·迈克尔·普莱奥; 杰弗里·迈克尔·阿舍; 戴维·安德鲁·肖迪; 维多利亚·尤金妮亚·科特罗; 詹姆斯·恩里科·萨巴蒂尼
Original assignee: General Electric Co
Current assignee: GE Precision Healthcare LLC
Priority date: 2019-07-19
Filing date: 2020-07-14
Publication date: 2022-03-01
Anticipated expiration: 2040-07-14
Also published as: US20240237966A1; US20210015454A1; WO2021015983A1; EP3999177A4; US11944490B2; JP2022540666A; EP3999177B1; CN114126703B; EP3999177A1; EP4385421A3; EP4385421A2

Abstract

Embodiments of the present disclosure relate to techniques for precise positioning of energy application devices for neuromodulation therapy protocols. In one embodiment, a neuromodulation site is applied to the skin of a patient. The energy application device is configured to be coupled to the frame of the neuromodulation site to position the transducer of the energy application device within the opening at the treatment location within the opening. In one embodiment, the frame is further configured to be coupled to a removable interface of an imaging probe that, when coupled to the removable interface and in turn the frame of the neuromodulation site, is configured to acquire image data through the opening to identify or verify a treatment location.

Description

Neuromodulation energy application techniques

Technical Field

The subject matter disclosed herein relates to techniques to support application of neuromodulation energy doses in a subject via application of neuromodulation energy to elicit a target physiological result. In particular, the disclosed technology can be part of a repeated dose regimen, a self-application regimen, and/or an in-home neuromodulation therapy regimen.

Background

Neuromodulation has been used to treat a variety of clinical conditions. For example, electrical stimulation at different locations along the spinal cord has been used to treat chronic back pain. However, positioning the electrodes at or near the target nerve is challenging. For example, such techniques may involve surgical placement of electrodes that deliver energy. Furthermore, specific tissue targeting via neuromodulation is challenging. Electrodes positioned at or near certain target nerves mediate neuromodulation by triggering action potentials in the nerve fibers, which in turn lead to neurotransmitter release at the neurite contacts and synaptic communication with the underlying nerve. This propagation may result in a relatively greater or more diffuse physiological effect than desired, as current implementations of implanted electrodes stimulate many nerves or axons simultaneously. Because neural pathways are complex and interconnected, more selective and targeted modulation effects may be more clinically useful. However, the effectiveness of selectively targeting a particular nerve may depend on the exact location of the energy application device.

Disclosure of Invention

The following outlines certain embodiments that are commensurate with the scope of the claimed subject matter. These embodiments are not intended to limit the scope of the claimed subject matter, but rather these embodiments are intended only to provide a brief summary of possible embodiments. Indeed, the present disclosure may encompass a variety of forms that may be similar to or different from the embodiments set forth below.

In one embodiment, a neuromodulation energy application system is provided that includes a neuromodulation site patch (patch). The neuromodulation site includes a conformable substrate including an application surface configured to be applied to the skin of a subject, the application surface including an adhesive portion, wherein the conformable substrate forms a first opening that allows a portion of the skin of the subject to be viewed through the first opening when the conformable substrate is applied. The neuromodulation site also includes an elastic frame (framework) disposed on the compliant layer to enclose the (framework) first opening and to protrude from a top surface of the compliant layer, the top surface being opposite the adhesive surface. The neuromodulation site also includes an abutment (dock) configured to removably mate with the resilient frame, wherein the abutment forms a shaped channel that terminates in a second opening, wherein the second opening is located within the first opening when the abutment is mated with the resilient frame. The neuromodulation energy application system also includes an ultrasound therapy probe configured to fit within or be coupled to the frame to apply neuromodulation energy to a region of interest of the internal tissue through a portion of the skin of the subject.

In another embodiment, a method is provided, comprising the steps of: acquiring image data of a subject; identifying or verifying a region of interest based on the acquired image data; determining a treatment location on the skin of the subject based on the region of interest; positioning a neuromodulation site on the skin of the subject such that an opening formed in the neuromodulation site is positioned on or over the treatment location; a therapy transducer coupling the ultrasound therapy probe to the neuromodulation site to pass through the opening and position the ultrasound therapy probe at the therapy location; and applying ultrasound energy from the ultrasound therapy probe to the treatment site region of interest through the treatment site.

In another embodiment, a neuromodulation site is provided that includes a compliant substrate including an opening extending through the compliant substrate; an adhesive disposed on the application surface of the conformable substrate; an elastic frame coupled to the substrate around a perimeter of the opening and protruding from a top surface of the compliant substrate, the elastic frame including one or more mating features; and at least one dock for the ultrasound imaging probe, the at least one dock configured to removably mate with the resilient frame via one or more complementary mating features that mate with the one or more mating features, wherein the dock forms a shaped channel that terminates in a second opening, wherein the second opening is located within the first opening when the dock mates with the resilient frame.

Drawings

These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:

FIG. 1 is a schematic diagram of a neuromodulation system using a pulse generator and a neuromodulation site, according to embodiments of the present disclosure;

figure 2 is a schematic view of a neuromodulation site and an abutment and an ultrasound imaging probe in an uncoupled configuration, according to embodiments of the present disclosure;

FIG. 3 is a schematic view of a neuromodulation site and an interface in accordance with embodiments of the present disclosure;

FIG. 4 is a schematic view of a neuromodulation site and an interface coupled to a probe according to embodiments of the present disclosure;

FIG. 5 is a schematic view of a neuromodulation site kit including different docking members for various configurations in accordance with embodiments of the present disclosure;

FIG. 6 is a schematic view of a neuromodulation site coupled to an ultrasound imaging probe via a docking piece according to embodiments of the present disclosure;

FIG. 7 is a schematic view of an empty or uncoupled neuromodulation site worn by a subject;

FIG. 8 is a schematic view of a neuromodulation site and an ultrasound therapy probe configured to be coupled to a frame of the neuromodulation site in an uncoupled configuration, according to embodiments of the present disclosure;

FIG. 9 is a bottom view of a neuromodulation site coupled to the ultrasound therapy probe of FIG. 8;

FIG. 10 is a bottom view of a frame of a neuromodulation site coupled to the ultrasound therapy probe of FIG. 8;

figure 11 is a component view of a neuromodulation site and an ultrasound therapy probe configured to be coupled to a frame of the neuromodulation site with a locking feature in accordance with an embodiment of the present disclosure;

FIG. 12 is a bottom view of a neuromodulation site having an integral combined ultrasound therapy and imaging probe according to embodiments of the present disclosure;

FIG. 13 is a flow diagram of a neuromodulation technique using a neuromodulation site, according to an embodiment of the present disclosure; and is

Fig. 14 is a block diagram of a neuromodulation system according to embodiments of the present disclosure.

Detailed Description

One or more specific embodiments will be described below. In an effort to provide a concise description of these embodiments, not all features of an actual implementation are described in the specification. It should be appreciated that in the development of any such actual implementation, as in any engineering or design project, numerous implementation-specific decisions must be made to achieve the developers' specific goals, such as compliance with system-related and business-related constraints, which may vary from one implementation to another. Moreover, it should be appreciated that such a development effort might be complex and time consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill having the benefit of this disclosure.

Any examples or illustrations given herein are not to be considered in any way as constraints, limitations, or express definitions of any term or terms with which they are employed. Rather, these examples or illustrations should be considered in relation to the different detailed description and are intended to be illustrative only. Those of ordinary skill in the art will understand that any term or terms used in these examples or descriptions will encompass other embodiments that may or may not be given together or elsewhere in this specification, and all such embodiments are intended to be included within the scope of that term or terms. Language designating such non-limiting embodiments and descriptions includes, but is not limited to: "for example," such as, "" such, "" including, "" in certain embodiments, "" in some embodiments, "and" in one (or the same) embodiment.

Techniques are provided herein for non-invasive neuromodulation of a target region of interest as part of a treatment plan that allow for reproducible and reliable application of energy to a particular region or regions of interest during the course of the treatment plan. Non-invasive neuromodulation may be applied via an energy application device (e.g., a therapy probe, an ultrasound therapy probe) that is positioned on the skin of the patient and delivers neuromodulation energy through the skin and to the region of interest. For certain patients, a treatment regimen may include applying energy (e.g., non-invasive ultrasound or mechanical energy application) to a region of interest of a patient at intervals according to the particular clinical needs of the patient and at doses related to the target physiological outcome. Depending on the length of the interval between energy applications (e.g., the interval is hours, days, or weeks), it may be inconvenient and cumbersome for the patient to receive neuromodulation energy at each treatment time in a physician's office or hospital. Therefore, it would be beneficial to allow a patient to receive neuromodulation energy at home or in a convenient out-patient setting via self-directed delivery or with the assistance of a family member or caregiver in accordance with a treatment regimen. However, because patients typically do not have the skill or training in the operation of medical devices, it can be challenging to train patients to manage their own neuromodulation therapy. In addition, the treatment plan for each patient may be personalized and varied from patient to patient according to variations in anatomy, patient clinical condition, and patient responsiveness to energy to produce a target physiological result. For example, a treatment regimen for treating a particular condition may target a particular region of interest (e.g., a region of the liver, pancreas, or other tissue). The effective energy application site associated with neuromodulation energy targeted to a region of interest may be at a site of one patient and at a slightly different site of another patient due to differences in patient anatomy. These sites may also include areas on the back or sides of the patient that are difficult to reach while maintaining the therapeutic probe and, if reached, difficult for the patient to target in an accurate manner with repeated doses. Furthermore, identifying a desired region of interest and an associated treatment location on the skin to achieve energy delivery to the region of interest may involve complex imaging devices that are not widely available and add time to each dose of a multi-dose treatment regimen.

The neuromodulation techniques disclosed herein facilitate identifying a treatment location on the skin of a patient for an energy application device, and positioning a neuromodulation site at or about the treatment location. For example, if a patient is prescribed a multi-dose treatment regimen that occurs over several days or weeks, the neuromodulation site may be applied to the patient at the beginning of the treatment regimen, and may remain in place until the treatment regimen is complete to facilitate proper positioning of the energy application device. The neuromodulation site includes a support structure that reversibly mates or mates with an energy application device (e.g., a therapy probe) and positions the energy application device at a therapy location for accurate targeting of a region of interest via application of neuromodulation energy. The treatment site is a location on the patient's body where the energy applied at (and through) the treatment site affects a desired region of interest in the patient's body to achieve a target physiological result when the energy application device is positioned at the treatment site as provided herein. Such techniques may guide patients and/or their caregivers to accurately administer their own treatments.

In one embodiment, the neuromodulation site can at least partially support and orient the therapy probe such that the patient or caregiver does not need to apply pressure or, in some embodiments, hold the therapy probe to maintain the therapy probe in the correct position. This may reduce variability in dosing that may be a result of different caregivers orienting and/or positioning the treatment probe at slightly different positions that are misaligned or partially aligned with the treatment location. Furthermore, differences in the pressure of the probe against the skin at the treatment site may also lead to undesirable variability in the applied dose. An additional benefit of the disclosed techniques is that the neuromodulation site allows for one-time identification of a region of interest and a treatment location on the skin of a patient. Once identified, the neuromodulation site is positioned in the appropriate location. In subsequent dose applications, there is no need to perform complex imaging related to the identification of the region of interest. Thus, the dose application is faster and can occur at home or in an outpatient setting without complex imaging devices, resulting in greater flexibility in receiving neuromodulation energy according to a treatment protocol. The neuromodulation site may be multifunctional and configured to be coupled to a therapy probe and an imaging probe via an adapter structure.

To this end, the disclosed neuromodulation techniques may be used with neuromodulation systems configured for administering neuromodulation energy as part of a treatment regimen. FIG. 1 is a schematic diagram of a system 10 that uses a neuromodulation site supporting an energy application apparatus to achieve a neuromodulation effect, such as neurotransmitter release and/or activation of a component of a synapse (e.g., a pre-synaptic cell, a post-synaptic cell) in response to application of energy. The depicted system includes a pulse generator 14 coupled to an energy application device 12 (e.g., an ultrasound therapy probe). The energy application device is coupled to a neuromodulation site 16 that is in place on the skin of the subject and holds or supports the energy application device 12 at the treatment location during application of the neuromodulation energy. The energy application device 12 is configured to receive, e.g., via a lead or wireless connection, an energy pulse that is directed, in use, to a region of interest 18 of an internal tissue or organ (e.g., peripheral tissue) of the subject, which in turn results in a target physiological outcome. In the depicted embodiment, the neuromodulation site 16 is positioned on the back of the patient in a difficult-to-reach location. However, it should be understood that the neuromodulation site 16 may be applied to align with the appropriate treatment site, depending on the clinical needs of the subject.

In certain embodiments, the energy application device 12 and/or the pulse generator 14 may communicate wirelessly, such as with the controller 20, which in turn may provide instructions to the pulse generator 14. In other embodiments, the pulse generator 14 may be integrated within the controller 20. The energy application device 12 is operable by a caregiver and positioned on or over the skin of the subject via the neuromodulation site 16 such that the energy pulse is delivered percutaneously to a desired internal tissue (e.g., a peripheral tissue including one or more peripheral axon tips). Once positioned to apply an energy pulse to a desired treatment location via coupling to the neuromodulation site 16, the system 10 may initiate neuromodulation of one or more neural pathways to achieve a target physiological result or clinical effect.

In certain embodiments, the system 10 may include an evaluation device 22 that is coupled to the controller 20 and evaluates a characteristic that indicates whether the adjusted target physiological result has been achieved. In one embodiment, the target physiological result may be local. For example, modulation of one or more neural pathways may result in local tissue or functional changes, such as tissue structural changes, local changes in the concentration of certain molecules, tissue displacement, increased fluid movement, and the like, as disclosed herein. The target physiological result may be a target of a treatment regimen. For example, the target physiological outcome may include hormone secretion (such as secretion of insulin from the pancreas or ghrelin from the GI), cell viability, and/or cell or hormone stability.

The neuromodulation site 16 may be used in conjunction with neuromodulation therapy protocols as provided herein. Neuromodulation of one or more neural pathways to achieve a target physiologic result can result in a systemic or non-local change, and the target physiologic result can be correlated with a change in the concentration of circulating molecules or a change in a characteristic of the tissue of the region of interest that does not include the direct application of energy. In one embodiment, the displacement may be a proxy measurement for the desired adjustment, and a displacement measurement below the desired displacement value may result in a modification of the adjustment parameter until the desired displacement value is caused. Thus, in some embodiments, the evaluation device 22 may be configured to evaluate a change in concentration. In some embodiments, the evaluation device 22 may be an imaging device configured to evaluate changes in organ size location and/or tissue characteristics. In some embodiments, the evaluation device 22 monitors changes in blood pressure, indicating changes in arterial resistivity that are relevant to the treatment. In another embodiment, the evaluation device 22 may be a circulating glucose monitor. Although the depicted elements of system 10 are shown separately, it should be understood that some or all of the elements may be combined with each other. In another embodiment, the evaluation device may evaluate a local temperature rise of the tissue, which may be detected using a separate temperature sensor from the energy application device 12 or ultrasound imaging data when configured for ultrasound energy application. Assessment of the speed of sound difference can be detected by pre-treatment/during treatment/post-treatment difference imaging techniques.

Based on this evaluation, the tuning parameters of the controller 20 can be changed such that an effective amount of energy is applied. For example, if the desired modulation is associated with a concentration change (cyclic concentration of one or more molecules or tissue concentration) within a defined time window (e.g., 5 minutes, 30 minutes after the start of the energy application procedure) or relative to a baseline at the start of the procedure, a change in a modulation parameter (such as pulse frequency or other parameter) may be desired, which in turn may be provided to the controller 20 by an operator or via an automatic feedback loop for defining or adjusting the energy application parameter or modulation parameter of the pulse generator 14 until the modulation parameter results in the application of an effective amount of energy.

The system 10 as provided herein can provide pulses of energy to apply an effective amount of energy according to various regulatory parameters as part of a treatment regimen. For example, the modulation parameters may include different stimulation time patterns ranging from continuous to intermittent. With intermittent stimulation, energy is delivered at a specific frequency for a period of time during the signal-on time. The signal-on time is followed by a period of no energy delivery, referred to as the signal-off time. The adjustment parameters may also include the frequency and duration of stimulus application. The application frequency may be continuous or delivered over different time periods (e.g., over a day or week). In addition, the treatment regimen may specify the time of day when energy is applied or relative to the time of eating or other activity. The duration of treatment that elicits the targeted physiological result may last for various periods of time, including, but not limited to, from minutes to hours. In some embodiments, the duration of treatment with the specified stimulation pattern may last one hour, repeating at 72 hour intervals, for example. In certain embodiments, energy may be delivered at a higher frequency, for example every three hours, for a shorter duration, for example 30 minutes. The application of energy according to regulatory parameters, such as treatment duration, frequency, and amplitude, can be adjustably controlled to achieve a desired result.

The energy application device 12 may be configured as an extracorporeal non-invasive device. The energy application device 12 may be an extracorporeal non-invasive ultrasound therapy probe comprising an ultrasound transducer or a mechanical actuator. For example, the energy application device 12 may be configured as a handheld ultrasound probe. Further, in addition to the handheld configuration, the energy application device 12 may include a steering mechanism (steering mechanisms) responsive to commands from the controller 20. The steering mechanism may direct or direct the energy application device 12 toward the region of interest 18, and the controller 20 may then focus the application of energy onto the region of interest 18.

In operation, the neuromodulation site 16 may be configured to hold or support the energy application device 12 during dose delivery. In addition, the neuromodulation site 16 is configured to hold or support an imaging probe to acquire images to identify or verify a desired treatment site. As provided herein, the imaging probe may be part of the system 10 and may also be operated using the same or similar components that control energy application via the energy application device 12. That is, the imaging probe may use the pulse generator 14 under the control of the controller 20. In one embodiment, an ultrasound therapy transducer and/or an imaging transducer as disclosed herein comprises a MEMS transducer, such as a capacitive micromachined ultrasound transducer. In one embodiment, the therapy transducer and the imaging transducer may be integrated within a single energy application device 12. However, in other embodiments, the energy application device 12 and the imaging probe are separate devices.

Because the energy application device 12 and the imaging probe can have different configurations, the neuromodulation site 16 includes features that adapt the neuromodulation site 16 for coupling to both types of devices. Figure 2 is a schematic diagram of a neuromodulation site 16 applied to a subject and configured to receive an imaging probe 28. The neuromodulation site 16 includes a compliant substrate 30, the compliant substrate 30 forming a hole or opening 32 therethrough to allow the patient's skin to be viewed through the opening 32 when the neuromodulation site 16 is applied (e.g., adhered) in place. The conformable substrate 30 may be formed of fabric, paper, or a conformable polymer. The opening 32 is surrounded by an elastic frame 34 that protrudes from a top surface 36 of the compliant substrate 30. The top surface 36 is opposite the surface of the compliant substrate 32 that is applied to the patient's skin.

In some embodiments, the neuromodulation site 16 is worn for several days. Thus, the compliant substrate 32 may be more comfortable to the subject than a rigid substrate. However, in certain embodiments, portions of the compliant substrate 32 may be replaced or reinforced with rigid elements to help support larger or heavier coupling probes.

In operation of the imaging configuration, the resilient frame 34 is configured to be coupled to the removable dock 40. Removable interface element 40 forms a channel that terminates in a distal opening 42 that receives imaging probe 28. Resilient frame 34 is coupled to removable interface element 40 such that distal opening 42 of interface element 40 is positioned within opening 32. In this manner, when coupled to the interface 40, the imaging transducer 46 of the imaging probe 28 is properly positioned at the treatment site 50. In one embodiment, the interface 40 is configured for direct contact with the patient's skin at the distal opening when coupled to the resilient frame 34. The resilient frame 34, the dock 40, and/or the imaging transducer 46 of the imaging probe 28 may include one or more mating features that facilitate their respective coupling. For example, the inner wall 52 of the resilient frame 34 may include one or more grooves or protrusions 54 configured to mate with complementary features 56 on the outer wall 68 of the interface element 40. Similarly, the outer wall 58 of the housing 59 of the imaging probe may also include one or more mating features 60 configured to mate with complementary features 62 on the inner wall 64 of the docking member 40. The resilient frame 34, the interface 40, and/or the imaging transducer 28 may be formed of a rigid or semi-rigid material, such as a polymer having a shore D hardness of 10-50.

As disclosed herein, mating features (e.g., mating features 54, 56, 60, 62) may be configured as grooves, recesses, protrusions, locking features, threaded features, snaps, and the like. Furthermore, certain components may additionally or alternatively be configured for an interference fit (interference fit). The mating features may also include one or more signal generators or indicators (e.g., RFID chips 57) that generate or provide a signal to indicate successful mating when mated with their complementary features. The mating features may be configured to allow the components to be mated in only one orientation with respect to each other. For example, the elastic frame 34 and the docking member 40 may be fitted to each other only in one direction. Further, the docking member 40 may also accommodate the imaging probe 28 in only one orientation. Such an arrangement may facilitate proper orientation of the imaging probe 28 within the neuromodulation site 16 and relative to the treatment site 50.

In the depicted configuration, the resilient frame 34 extends a distance 70 (e.g., less than 3cm, less than 1cm) from the top surface 36. The protrusion is in a direction away from the subject. In certain embodiments, it is desirable for the elastic frame 34 to have a relatively low profile so that the subject causes less discomfort over time. Further, by configuring the dock 40, which may have a relatively large profile, to be removable, the neuromodulation site 16 may only be temporarily configured in a higher profile (greater protrusion from the skin) imaging configuration. In other embodiments, the resilient frame 34 may be configured with telescoping or adjustable height walls 52 such that the resilient frame 34 may be switched between an undocked or empty configuration having a lower profile relative to a docked or operational configuration.

The initial positioning of the neuromodulation site 16 on the patient may be performed by the imaging technician or the physician. The operator acquires the image until an image is acquired that includes the region of interest 18. The position of the imaging probe 28 on the skin when acquiring the image of the region of interest 18 may correspond to the treatment location 50. In one embodiment, an indicator 74 (such as a mark, temporary tattoo, or sticker) may be applied to the skin of the treatment location 50 to guide the proper positioning of the opening 32 to align with the treatment location 50, i.e., to be positioned on or over the treatment location 50. In addition, the indicator 74 can be shaped to align with the opening 32 to assist in the proper positioning of the neuromodulation site 16. In one embodiment, the neuromodulation site 16 may be configured to apply and/or refresh the indicator 74. For example, the compliant substrate 30, the elastic frame 34, and/or the removable interface 40 can include an ink or other transferable material configured to mark the subject when the neuromodulation site 16 is applied. Because the neuromodulation site 16 can be moved along the subject to try several locations before finally adhering in place, the transferable material can be actuated or triggered via a user action. For example, the transferable material may be pressure-sensitive and may be applied upon application of sufficient pressure. In another embodiment, successful mating of the removable interface element 40 and the resilient frame 34 opens a reservoir within the removable interface element 40 and the resilient frame 34 that contains transferable material and is open to the patient contacting side of the neuromodulation site 16. In another embodiment, the user presses a button or actuator to release the transferable material. In this manner, the desired location of the neuromodulation site 16 can be marked so that a new neuromodulation site 16 can be applied to the subject when the previous device is due for replacement.

After identifying the desired treatment site 50, the indicator 74 is applied to mark the preferred location of the neuromodulation site 16. Such identification may constitute a first pass positioning (pass positioning) that allows the subject or operator to affix the neuromodulation site 16 in the correct position based on the imaging data. However, additional imaging data may be required to verify the treatment location 50 and/or to acquire information for fine manipulation of the treatment probe. That is, the imaging probe 28 supported by the neuromodulation site 16 at the treatment site 50 may additionally or alternatively acquire imaging data to verify the treatment site 50 and/or be provided to the treatment probe for manipulation of the ultrasound treatment beam by the controller 20. It should be understood that the treatment location 50 as provided herein may include the angle, orientation, and/or pose of the energy application device 12. The location information may also include an assessment of contact or pressure on the subject.

In certain embodiments, the ultrasound imaging probe 28 may be any suitable probe capable of acquiring image data of internal tissue near and around the target tissue containing the region of interest 18. If the first pass image acquisition for the initial positioning of the neuromodulation site 16 is successful, a lower complexity ultrasound imaging probe 28 may be used to acquire additional verification or beam steering image data. For example, images from a high resolution first pass may be accessed and used to supplement additional lower quality image data. Thus, the caregiver may have flexibility in image resolution capabilities when selecting an available ultrasound image probe 28 to acquire additional image data. Thus, a more commonly available lower complexity ultrasound image probe 28 may be suitable.

Figure 3 illustrates the neuromodulation site 16 with a mating removable interface 40 that is ready to receive a probe, such as the imaging probe 28, as shown in the mated configuration of figure 4. The probe is inserted through the proximal opening 80 of the removable dock 28. While the embodiment depicted in fig. 4 shows a mated imaging probe 28, it should be understood that in an embodiment, the removable interface 40 may also be configured to receive a treatment probe. Furthermore, in embodiments where the imaging probe 28 and the therapy probe are implemented as an integral device, the removable interface 40 or a different removable interface 40 may receive the integral device.

The removable dock 40 provides resilient support to a mating probe (e.g., imaging probe 28) to maintain a desired orientation of the probe relative to the subject. The inner wall 64 directly contacts and supports the probe housing 59 to maintain orientation along a desired axis, such as an axis 82 through the housing 59, and aligned with the direction of the applied energy 84. The probe may be maintained to avoid tilting (e.g., along arrow 86) such that the energy applied during activation of the probe is generally along the stabilization axis. In addition, the mating features 62 of the docking member may also be used to facilitate positioning of the probe. The outer wall 68 of the interface element 40 is defined by a height 81, and the height 81 increases the contour of the neuromodulation site 16 beyond the distance 70 that the frame 34 extends from the compliant base. In one embodiment, the interface element 40 has a distal recess or groove that mates with the resilient frame 34. In such an embodiment, the mating interface 40 overlaps the resilient frame 34. The distance 81 is greater than the distance 70 that the frame 34 extends from the compliant substrate 30. In one embodiment, the height 81 of the interface element 40 is at least 2 times, 2.5 times, or 3 times the distance 70. As discussed herein, the increase in the profile of the neuromodulation site 16 with the mating interface 40 is temporary.

The positioning and adherence of the patch 16 on the patient sets the x-y position and rotation of the probe (e.g., the energy application device 12 and/or the imaging probe 28). In another embodiment, the interface 40 or frame 34 may allow fine adjustment of the tilt, shake and/or compression (pressure on the skin) of the probe. For example, the interface 40 or the frame 34 may include a compressible foam or putty disposed on the inner wall 64 that allows for steering of the probe (e.g., along arrow 86) until a desired direction is achieved. The desired direction may be associated with improved acquired image data and/or improved contact with or pressure applied to the skin of the subject. The putty or foam holds the probe in the desired orientation. In other embodiments, the interface 40 or frame 34 may include other features that allow for adjustment of the probe orientation, such as compressible or memory metal walls. In another embodiment, the orientation may be adjusted by locking adjustable mechanical linkages, specifically tilt, rock and compress, in each adjustable dimension. For compression, the Z position at which the probe is set (e.g., along axis 82) may be adjusted so that when the probe is locked into the dock, the probe face may be pushed (push past) through the frame 34 of the wearable patch 16 into the skin to ensure good contact or to achieve a particular target contact force. The positioning of the probe relative to the frame 34 may allow for several different positions of the slots along the axis 82. In one embodiment, the frame 34 and/or the interface 40 may include two or more internal mating features 54, 56, such as grooves, at different locations along the Z-axis. The groove may be configured to be at least partially conformable (formed with a flexible edge) such that a user may push through successive mating features 54, 56 with moderate force until a desired position of the probe along axis 82 is achieved. In another embodiment, the probe, frame 34, and/or dock 40 may include deployable locking features. For example, the probe may be adjusted within the docking member 40 or frame 34 (in embodiments without the docking member 40) until the desired position is reached. The user may then press a button on the dock 40 or frame 34 which causes actuation of a locking feature towards the probe contacting the probe housing or a mating feature on the probe to lock the probe in place.

Fig. 5 is a schematic view of a neuromodulation site kit including different interfaces 40 that mate with differently shaped ultrasound imaging probes 28 to facilitate use of multiple types and/or configurations. In one embodiment, the neuromodulation site 16 may be provided as a kit with different types of docking members 40, the docking members 40 being selectable based on the available imaging modalities. The caregiver may wish to use available or familiar imaging equipment to acquire image data that allows for verification of the initial positioning and/or post-positioning position of the neuromodulation site 16. By providing an exchangeable docking piece 40 comprising a channel 87 of different shape, a variety of available imaging probes can be used. In the depicted embodiment, the

different abutments

40a, 40b, 40c, 40d can be shaped such that their outer walls 68 are substantially identical to allow each of the

different abutments

40a, 40b, 40c to mate with the resilient frame 34. In one embodiment, the non-mating portions of outer wall 68 may vary in size and shape between different docking members 40. Further, each of the

different abutments

40a, 40b, 40c, 40d may include the same mating features on their outer walls 68. In an alternative embodiment, each of the

different abutments

40a, 40b, 40c, 40d may include a unique mating feature 56 that, when mated with the resilient frame, triggers the activation of a particular type of identification signal of the abutment 40, which in turn may be provided to its controller (e.g., controller 20) by the ultrasound imaging probe 28 as a verification procedure.

The

internal shaping channels

87a, 87b, 87c, 87d are configured such that only certain or specific types of ultrasound imaging probes 28 will fit within each individual docking piece 40, and in one embodiment, will fit only in a specific orientation. The inner shaping channel 87 may include grooves, notches, or other shaping features associated with a particular type of ultrasound imaging probe 28. In one embodiment, the kit may also include a universal dock 40 having a larger or generally annular channel 87 that allows for insertion of multiple types of ultrasound imaging probes 28. The shaped channels terminate in respective distal openings 42 that position the transducers 46 at the desired treatment (or imaging) location. The individual abutments 40 can also be sized and shaped to allow the operator to try different probe angles or orientations. For example, certain internal channels 87 may be oriented at different angles relative to one another (e.g., internal channel 87a and internal channel 87d) such that the retained probes are correspondingly held at different angles. In addition, the kit may include one or more adjustable abutments 40, the adjustable abutments 40 allowing the probe to move within the internal channel 87 until the desired position is reached. For example, a docking member 40 having an oversized or universally sized internal channel 87 may be equipped with a gasket, foam, gel, locking mechanical connection, or other temporary stabilizing material that may be inserted into the internal channel 87 in order to fill any gaps between the inner wall 64 and the housing 59 of the probe and in order to maintain the probe in a desired orientation.

The kit may also include a plurality of neuromodulation site patches 16, e.g., of different sizes and shapes for application to different treatment sites. Further, it should be understood that certain components of the kit may be disposable (the neuromodulation site 16), while other components may be reusable (the docking component 40).

Fig. 6 is a schematic view of the neuromodulation site 16 coupled to the ultrasound imaging probe 28 via the interface 40 in a coupled or imaging configuration. In the coupled configuration, the imaging transducer 46 of the ultrasound imaging probe 28 is aligned with a treatment location 50 on the patient's skin and imaging energy may be applied. As shown, when mated with resilient frame 34, docking member 40 may also provide support to ultrasound imaging probe 28 to hold ultrasound imaging probe 28 at a desired pressure and in a desired position and orientation relative to treatment site 50 during acquisition of image data. After the acquisition of image data is complete, the docking member 40 and the ultrasound imaging probe 28 may be removed from the neuromodulation site 16 so that the subject may continuously wear only the less complex and less expensive components of the system 10, which may be easily replaced if damaged.

Fig. 7 is a schematic view of an empty or uncoupled neuromodulation site 16 worn by a subject. In the uncoupled configuration, the neuromodulation site 16 may include only the compliant substrate 30 and the elastic frame 34. As discussed herein, the compliant substrate 30 may be reinforced by one or more rigid or semi-rigid layers or structures to maintain the integrity of the location of the neuromodulation site 16 on the skin of the subject and to support any mating structures. The resilient frame 34 may be of relatively low profile for comfort and may be rounded or may include cushioning or bumpers to prevent discomfort when pressed. As described above, in the uncoupled configuration, the neuromodulation site 16 is ready to receive either the ultrasound imaging probe 28 or the energy application device, depending on the next step in the treatment plan. It should be understood that patch 16 may be used in conjunction with a variety of treatment regimens, such as those occurring over days, weeks, months, or even years. The patch 16 may be configured to be replaced as needed, and a new patch 16 may be applied to the subject according to the techniques provided herein. In addition, additional image acquisitions during treatment may be used to spot check the initial placement of the patch 16. Still further, additional images may be acquired such that patch placement may be responsive to changes in the subject's physiology over time. For example, ultrasound treatment for metabolic disorders according to the techniques herein can result in weight loss, which can affect proper patch positioning by changing the depth of the region of interest relative to the skin.

While the compliant substrate 30 is depicted as having a generally annular configuration, it should be understood that other shapes are contemplated, including elongated shapes, rectangles, irregular shapes, and the like. For example, a particular treatment site 50 may be associated with a particular shape of the compliant substrate 30 to achieve a desired adhesion. Further, the opening 32 and the elastic frame 34 are depicted as being generally rectangular. However, depending on the size of the treatment site 50 and the size and shape of the energy application device 12 and the ultrasound imaging probe 28, the opening 32 and the resilient frame 34 may be configured in a ring shape, an elongated shape, a rectangle, an irregular shape, and the like.

Further, the perimeter of the opening 32 may be entirely defined by the resilient frame 34, or may be largely defined (e.g., at least 75% defined). In one embodiment, the compliant base 30 and the elastic frame 34 can form a U-shape that allows a sliding action to couple the energy application device 12 and/or the ultrasound imaging probe 28 to the neuromodulation site 16.

Fig. 8 is a schematic view of a neuromodulation site and an energy application device 12, the energy application device 12 configured as an ultrasound therapy probe configured to be coupled to the resilient frame 34 of the neuromodulation site 16 in an uncoupled configuration. Fig. 9 is a bottom view of the neuromodulation site 16 coupled to the energy application device 12 of fig. 8 (i.e., in the coupled configuration). Fig. 10 is a bottom view of the positioning of the transducer 95 of the energy application device 12 within the elastic frame 34, wherein the energy application device 12 is mated to fill the opening 32 formed by the frame 34. The coupling may be via a mating feature 54 of the resilient frame 34, the mating feature 54 also being coupled to the dock 40 such that the mating feature 54 is received and coupled to the dock 40 and is configured to be coupled to a complementary mating feature 90 formed in or disposed on a housing 91 of the energy application device 12. The coupling may also be via a separate dedicated mating feature that is distinguishable (e.g., in a different location, size, or shape) from the interfacing mating feature of the resilient frame 34 and configured to couple to the complementary mating feature 90. One or both of the mating features of the energy application device 12 and the resilient frame 34 may include a signal element (such as connector 92 and connector 94) that is activated by the coupling and sends a signal indicating a successful coupling. For example, the

connectors

92, 94 may make direct contact when coupled to complete a circuit that is activated to send a signal when completed. When coupled, the energy application device 12 may be at least partially supported by the elastic frame 34 and the compliant base 30 to remain in place within the opening 32 and position the therapy transducer 95 during energy application such that a bottom surface 96 of the therapy transducer 95 is in contact with the patient's skin.

The applied layer 97 of the neuromodulation site 16 includes an adhesive 99, and the adhesive 99 may at least partially cover the applied layer 97 and serve to adhere the neuromodulation site 16 to the skin of the patient. In one embodiment, the adhesive is disposed on at least 50% of the surface area of the applied layer 97. In one embodiment, the application layer 97 includes a coupling gel region 98 comprising an ultrasonic gel disposed on the application layer. The ultrasound gel may be pushed into the opening 32 as the neuromodulation site 16 is applied. Thus, in certain embodiments, the energy application device 12 and/or the imaging probe 28 may directly contact the skin of the patient. It should be understood that direct contact may include coupling the skin to the probe head via a thin layer of ultrasound gel, as provided herein. The neuromodulation site 16 may also include a release layer (not shown) that covers the application layer 97 during storage to retain the adhesive 99 and the coupling gel 98. When present, the release layer is removed prior to application of the neuromodulation site 16.

Fig. 11 is an exploded view of an embodiment of the neuromodulation site 16 configured to be reversibly coupled to an energy application device 12 including an ultrasound therapy transducer 95. The housing 91 of the energy application device 12 holds both the therapeutic ultrasound transducer 95 and the extension spring 100, with the extension spring 100 positioned between a top surface 102 of the therapeutic ultrasound transducer 95 and an inner surface 103 of the housing 91. In this manner, the bottom surface 96 of the therapy transducer 95 can be held against the skin of the patient with tension (e.g., light pressure) when the energy application device is coupled to the frame 34 of the neuromodulation site 16.

The coupling may be between a mating feature 90 (such as a protrusion) of the housing 91 of the energy application device 12, which mating feature 90 is configured to lock with a complementary feature 54 of the frame 34, and a complementary feature 54 (such as a shaped channel 104) of the frame 34. In the depicted embodiment, the coupling may be a twist lock arrangement to place the energy application device 12 within the opening 32 of the frame 34 and position the protrusion within a lock region 105 extending away from the channel opening of the forming channel 104. However, other coupling arrangements (e.g., threaded coupling, snap fit, etc.) are also contemplated. The frame 34 may also include an opening configured to receive the cable 108 of the ultrasound therapy transducer 95. In this manner, the ultrasound therapy transducer 95 may be properly aligned with the frame 34 when the cable 108 is placed within the opening 106 and the complementary mating features 54, 90 are coupled.

Figure 12 is a bottom view of the neuromodulation site 16 showing the applied layer 97 and having the ultrasound therapy transducer 95 and the imaging transducer 46 in an integral combination according to embodiments of the present disclosure. While certain embodiments of the present disclosure are discussed in the context of removable or exchangeable components of the neuromodulation site 16, the neuromodulation site 16 may also be implemented as a multifunctional, unitary device. The imaging transducer 46 may be used for spatial selection of the region of interest 18 within the target tissue and verification of the location of the therapy transducer 95 applying the neuromodulation energy.

Figure 13 is a flow chart of a neuromodulation method 110 using a neuromodulation site 16, according to embodiments of the present disclosure. The method 100 may include the step of acquiring image data for identifying the treatment site 50. In one embodiment, image data is acquired in conjunction with a neuromodulation site 16. However, in other embodiments, the image data is previously acquired or acquired during a separate procedure. For example, the method 100 may include the step of applying the neuromodulation site 16 to the skin of the patient at the treatment location 50 (block 112). As provided herein, the applying step can include a pre-positioning step in which the neuromodulation site 16 is in a temporary or non-adherent position. While the neuromodulation site 16 can be configured for direct application to the skin, it is also contemplated that in certain embodiments, there can be an intermediate structure (e.g., a tissue layer) between the neuromodulation site 16 and the skin. As discussed herein, the initial positioning and application of the skin may be based on previously acquired image data. In another embodiment, the neuromodulation site 16 may be temporarily positioned on the skin (i.e., not adhered in place) until the correct treatment location 50 is identified via the acquired image data. After identification, the neuromodulation site 16 may then be adhered in place. During identification of the treatment location and/or acquisition of other image data occurring throughout the treatment process, the dock 40 may be coupled to or mated with the flexible frame 34 (block 114), and the ultrasound imaging probe 28 may be inserted into the dock (block 116) to acquire image data at the treatment location or at a potential treatment location (block 118) to evaluate the acquired image data to determine whether the potential treatment location is the treatment location 50. In one embodiment, the neuromodulation site 16 is in the non-adhesive configuration, and the imaging probe 28 is docked within the neuromodulation site 16 and activated to acquire image data. The neuromodulation site 16 is adjusted to change position on the subject's skin to move the docked imaging probe 28 until the treatment site 50 is identified. Once the neuromodulation site 16 is in place, the release liner covering the adhesive 99 can be removed to secure the neuromodulation site 16 in place.

In another embodiment, the imaging probe 28 may be used without the neuromodulation site 16 for a first period of time to facilitate coarse position adjustment. Once the imaging probe is proximate to the treatment site 50, the imaging probe 28 can be coupled to the removable interface 48 and the neuromodulation site 16.

Subsequently, the imaging probe 28 and the dock 40 are removed from the resilient frame 34 (block 120), for example, via breaking the complementary mating features or applying a force to overcome the interference fit. The empty resilient frame 34 is then mated to the energy application device 12 (e.g., an ultrasound therapy probe) to position the therapy transducer at the therapy location 50 (block 122). Once mated, ultrasound therapy energy (neuromodulation energy) is applied (block 124).

Fig. 14 is a block diagram of certain components of system 10. As provided herein, the system 10 for neuromodulation may include a pulse generator 14, the pulse generator 14 adapted to generate a plurality of energy pulses for application to tissue of a subject. The pulse generator 14 may be separate or may be integrated into an external device, such as the controller 20. The controller 20 includes a processor 130 for controlling the apparatus. Software codes or instructions are stored in the memory 132 of the controller 20 for execution by the processor 130 to control the various components of the apparatus. The controller 20 and/or the pulse generator 14 may be connected to the energy application device 12 via one or more leads 133 or wirelessly. As disclosed herein, the control of the energy application device 12 can further use input from one or more mating features 92 to detect successful mating of the energy application device 12 and the neuromodulation site 16.

The controller 20 also includes a user interface having an input/output circuit 134 and a display 136 adapted to allow the clinician to provide selection inputs or adjustment parameters to the adjustment program. Each adjustment routine may include one or more sets of adjustment parameters including pulse amplitude, pulse width, pulse frequency, and the like. Pulse generator 14 modifies its internal parameters in response to control signals from controller device 20 to change the stimulation characteristics of the energy pulses emitted through lead 133 to the subject to which energy application device 12 is applied. Any suitable type of pulse generating circuit may be employed including, but not limited to, constant current, constant voltage, multiple independent current or voltage sources, etc. The energy applied is a function of the current amplitude and the pulse width duration. The controller 20 allows for adjustable control of the energy by changing the tuning parameters and/or enabling energy application at a particular time or disabling/disabling energy application at a particular time. In one embodiment, the adjustable control of the amount of energy applied by the energy application device is based on information about the concentration of one or more molecules (e.g., circulating molecules) in the subject. If the information is from the evaluation device 22, a feedback loop may drive the adjustable control. For example, a diagnosis may be made in response to neuromodulation based on the circulating glucose concentration measured by the evaluation device 22. When the concentration is above a predetermined threshold or range, the controller 20 may initiate a treatment regime of energy application to a region of interest (e.g., the liver) and have an adjustment parameter associated with a decrease in circulating glucose. The treatment protocol may use different conditioning parameters (e.g., higher energy levels, more frequent applications) than those used in the diagnostic protocol.

In one embodiment, the memory 132 stores different operating modes selectable by an operator. For example, the stored operating mode may include instructions for executing a set of adjustment parameters associated with a particular treatment site (such as a region of interest in the liver, pancreas, gastrointestinal tract, spleen). Different sites may have different associated regulatory parameters. Rather than having the operator manually enter the mode, the controller 20 may be configured to execute the appropriate instructions based on the selection. In another embodiment, the memory 132 stores operating modes for different types of processes. For example, activation may be associated with a different stimulation pressure or frequency range relative to the stimulation pressure or frequency range associated with inhibiting or blocking tissue function.

In a particular embodiment, when the energy application device 12 is an ultrasound transducer, the effective amount of energy may relate to a predetermined time-averaged intensity applied to the region of interest. For example, an effective amount of energy may include a time-averaged power (time-averaged intensity) and a positive peak pressure in the range of 1mW/cm 2-30,000 mW/cm2 (time-averaged intensity) and 0.1MPa to 7MPa (peak pressure). In one embodiment, the time-averaged intensity is less than 35W/cm2 in the region of interest to avoid levels associated with thermal injury & ablation/cavitation. In another specific embodiment, when the energy application device is a mechanical actuator, the vibration amplitude is in the range of 0.1 to 10 mm. The selected frequency may depend on the mode of energy application, such as ultrasonic or mechanical actuators. The controller 20 may be capable of operating in a verification mode to acquire a treatment position, and the treatment position may be implemented as part of a treatment operating mode configured to execute a treatment protocol when the energy application device 12 is positioned at the treatment position.

The system may also include an imaging device (e.g., an ultrasound imaging probe 28) that facilitates focusing the energy application device 12. In one embodiment, the imaging device may be integrated with the energy application device 12 or the same device as the energy application device 12, such that different ultrasound parameters (frequency, aperture, or energy) are applied for selecting (e.g., spatially selecting) a region of interest and for focusing the energy to the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 132 stores one or more targeting or focusing modes for spatially selecting a region of interest within an organ or tissue structure. The spatial selection may include selecting a sub-region of the organ to identify a volume of the organ corresponding to the region of interest. The spatial selection may depend on the image data as provided herein. Based on the spatial selection, the energy application device 12 may focus on a selected volume corresponding to the region of interest. For example, the energy application device 12 may be configured to first operate in a verification mode to acquire a treatment location by acquiring image data identifying the treatment location associated with acquiring the region of interest. The verification pattern energy is not applied at a level and/or with modulation parameters suitable for neuromodulation therapy. However, once the region of interest is identified, the controller 20 can operate in a therapy mode according to the adjustment parameters associated with achieving the target physiological result.

The controller 20 may also be configured to receive an input related to the target physiological result as an input to the selection of the adjustment parameter. For example, when the imaging modality is used to assess a tissue feature, the controller 20 may be configured to receive a calculated indicator or parameter of the feature. Based on whether the indicator or parameter is above or below a predefined threshold, a diagnosis may be made and an indication of the diagnosis may be provided (e.g., via a display). In one embodiment, the parameter may be a measurement of tissue displacement of the affected tissue or a measurement of depth of the affected tissue. Other parameters may include assessing the concentration of one or more molecules of interest (e.g., assessing one or more changes in concentration relative to a threshold or baseline/control, rate of change, determining whether the concentration is within a desired range). Further, the energy application device 12 (e.g., an ultrasound transducer) is operable under the control of the controller 20 to a) acquire image data of the tissue, which can be used to spatially select a region of interest within the target tissue; b) applying modulation energy to the region of interest; and c) acquiring images to determine that a target physiological result has occurred (e.g., via displacement measurements). In such an embodiment, the imaging device, the evaluation device 22 and the energy application device 12 may be the same device.

The desired target tissue including the region of interest 18 (see fig. 1) may be an internal tissue or organ including axonal terminals and synapses other than neuronal cells. Synapses may be stimulated by applying energy directly to axon terminals within a focused field or focal zone of an ultrasound therapy transducer 95 (which is focused on a region of interest 18 of a target tissue) to cause the release of molecules into the synaptic space, e.g., the release of neurotransmitters and/or changes in ion channel activity to cause downstream effects. The region of interest 18 may be selected to include a certain type of axon terminal, such as an axon terminal of a particular neuron type and/or an axon terminal that synapses with a certain type of non-neuronal cell. Thus, the region of interest 18 may be selected to correspond to a portion of the target tissue having a desired axon tip (and associated non-neuronal cells). Energy application may be selected to preferentially trigger release of one or more molecules (such as neurotransmitters) from nerves within the synapse, or to directly activate non-neuronal cells themselves by direct energy transduction (i.e., mechanical transduction or voltage-activated proteins within non-neuronal cells), or to cause activation within the nerve and non-neuronal cells that results in a desired physiological effect. The region of interest 18 may be selected as a nerve site for accessing an organ. In one embodiment, liver stimulation or modulation may refer to modulation of the region of interest 18 at or near the hepatic portal. The acquisition of the treatment position 50 may include the selection of the region of interest 18, whereby the position of the region of interest 18 on the patient's body within the focal zone of the energy application device 12 when in operation is the treatment position 50.

The energy may be focused or substantially focused on the region of interest 18 and only on a portion of the internal tissue, for example less than about 50%, 25%, 10%, or 5% of the total volume of tissue. That is, the region of interest 18 may be a sub-region of internal tissue. In one embodiment, energy may be applied to two or more regions of interest 18 in the target tissue, and the total volume of the two or more regions of interest 18 may be less than about 90%, 50%, 25%, 10%, or 5% of the total volume of the tissue. In one embodiment, the energy is applied to only about 1% -50% of the total volume of the tissue, only about 1% -25% of the total volume of the tissue, only about 1% -10% of the total volume of the tissue, or only about 1% -5% of the total volume of the tissue. In certain embodiments, only axonal ends in the region of interest 18 of the target tissue will receive applied energy directly and release neurotransmitters, while non-stimulated axonal ends outside the region of interest 18 do not receive a large amount of energy and are therefore not activated/stimulated in the same manner. In some embodiments, axonal ends in tissue portions that receive energy directly will induce altered neurotransmitter release. In this way, the tissue sub-regions may be targeted for neuromodulation in a granular manner, e.g., one or more sub-regions may be selected. In some embodiments, the energy application parameters may be selected to induce preferential activation of neural or non-neuronal components within tissue that receives energy directly to induce a desired combined physiological effect. In certain embodiments, the energy may be focused or concentrated to less than about 25mm³Within the volume of (a). In certain embodiments, the energy may be focused or concentrated to about 0.5mm³-50mm³Within the volume of (a).However, other focal volumes are also contemplated based on the desired physiological result. The focal volume and depth of focus for focusing or concentrating energy within the region of interest 18 may be influenced by the size/configuration of the energy application device 12. The focal volume of the energy application may be defined by the focal field or focal zone of the energy application device 12.

As provided herein, energy may be applied substantially only to the region or regions of interest 18 in order to preferentially activate synapses in a targeted manner to achieve a target physiological result. Thus, in certain embodiments, only a subset of the plurality of different types of axon ends in the tissue are exposed to direct energy application.

In certain embodiments, the target tissue comprising the region of interest 18 is an internal tissue or organ comprising a peripheral nerve terminal or a peripheral axon terminal. Contemplated tissue targets include Gastrointestinal (GI) tissue (stomach, intestine), muscle tissue (heart, smooth and skeletal), epidermal tissue (epidermis, organ/GI lining), connective tissue, glandular tissue (exocrine/endocrine), and the like. In one embodiment, the focused application of energy at the neuromuscular junction promotes neurotransmitter release at the neuromuscular junction without an upstream action potential. In one embodiment, contemplated regulatory targets may include the pancreatic portion responsible for controlling insulin release or the liver portion responsible for sensing glucose/metabolites and/or adjusting their circulating concentrations.

While certain embodiments are disclosed in the context of ultrasonic energy application, it should be understood that other energy types are contemplated, such as mechanical energy. Thus, the energy application device 12 may be configured as a mechanical vibrator to apply neuromodulation energy. Furthermore, although certain embodiments of the present disclosure are discussed in the context of ultrasound imaging data, the system 10 may be implemented to acquire alternative or additional types of imaging data to direct the application of energy to the region of interest 18.

This written description uses examples to disclose certain embodiments, including the best mode, and also to enable any person skilled in the art to practice the disclosed embodiments, including making and using any devices or systems and performing any incorporated methods. The scope of the patent is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

1. A neuromodulation energy application system comprising:

Neuromodulation targeting patches, including:

a conformable substrate comprising an application surface configured to be applied to the skin of a subject, the application surface comprising an adhesive portion, wherein the conformable substrate forms a first opening, when the conformable substrate is applied When basal, the first opening allows viewing of a portion of the subject's skin through the first opening;

an elastic frame disposed on the conformable base to enclose the first opening and protruding from a top surface of the conformable base opposite the adhesive surface;

an abutment piece configured to removably mate with the resilient frame, wherein the abutment piece forms a shaped channel terminating in a second opening, wherein when the abutment piece mates with the resilient frame , the second opening is located within the first opening; and

An ultrasound therapy probe configured to fit within or be coupled to the frame to apply neuromodulation energy through a portion of the subject's skin to a region of interest in internal tissue.

2. The system of claim 1, wherein the shaping channel is configured to accommodate an ultrasound imaging probe configured to acquire ultrasound image data to identify when positioned within the shaping channel the region of interest.

3. The system of claim 1, wherein the interface is one of a plurality of interfaces, each individual interface of the plurality of interfaces having a correspondingly different type of ultrasound configured to accommodate Different shaped channels of the imaging probe.

4. The system of claim 1, wherein the applied layer comprises an ultrasonic gel portion.

5. The system of claim 1, wherein the frame includes one or more mating features configured to interface with the docking member or the ultrasound therapy probe One or more complementary features cooperate reversibly.

6. The system of claim 5, wherein the ultrasound therapy probe includes a housing supporting an ultrasound therapy transducer and having the one or more complementary features, wherein the housing is configured to Reversibly engage the frame via the one or more complementary features to cover the opening and orient the ultrasound therapy transducer toward the patient's skin.

7. The system of claim 6, wherein the one or more mating features of the frame are configured to mate with the one or more complementary features of the housing in only one direction .

8. The system of claim 7, wherein the only one orientation positions the ultrasound therapy transducer within the frame at the position when coupled to the docking member mating with the frame at the same location as the imaging transducer of the ultrasound imaging probe.

9. The system of claim 6, wherein the ultrasound therapy probe is a wireless probe, and wherein one or more batteries are positioned on or in the housing.

10. The system of claim 6, wherein the ultrasound therapy probe is a wired probe coupled to a power source via a cable extending from the housing.

11. The system of claim 5, wherein the ultrasound therapy probe is configured to detect coupling with the one or more complementary features of the frame and provide a signal indicative of the coupling.

12. The system of claim 11, wherein the ultrasound therapy probe is configured to cease applying neuromodulation energy when the coupling is not detected.

13. The system of claim 1, wherein the frame or the docking member includes a mechanical lock that, when activated, holds the probe's transducer in position against the probe. Subjects under fixed contact pressure.

14. The system of claim 1, wherein the frame or the docking member includes a mechanical lock that, when activated, locks the probe relative to the subject and/or Or remain in a fixed orientation relative to the neuromodulation positioning patch.

15. A method comprising:

obtain image data of the subject;

Identify or verify a region of interest based on the acquired image data;

determining a treatment location on the subject's skin based on the region of interest;

positioning a neuromodulation positioning patch on the subject's skin such that an opening formed in the neuromodulation positioning patch is positioned on or over the treatment site;

coupling an ultrasound therapy probe to the neuromodulation positioning patch to position a therapy transducer of the ultrasound therapy probe through the opening and at the treatment site; and

Ultrasound energy is applied from the ultrasound therapy probe through the treatment site to a treatment site region of interest.

16. The method of claim 15, comprising:

separating the ultrasound therapy probe from the neuromodulation positioning patch; and

The ultrasound therapy probe is recoupled to the neuromodulation positioning patch to apply additional ultrasound energy from the ultrasound therapy probe, the additional ultrasound energy being associated with the next planned dose.

17. The method of claim 15, wherein acquiring image data of the subject comprises coupling an ultrasound imaging probe to a removable docking piece of the neuromodulation positioning patch to attach the ultrasound imaging probe to The imaging transducer is positioned within both the docking piece opening and the opening of the neuromodulation positioning patch.

18. The method of claim 17, comprising separating the removable docking member from the frame of the neuromodulation positioning patch.

19. The method of claim 15, wherein coupling the ultrasound therapy probe to the neuromodulation positioning patch comprises coupling a mating feature of the ultrasound therapy probe to the neuromodulation positioning patch Complementary mating features of a resilient frame of , wherein the frame is positioned around the perimeter of the opening.

20. The method of claim 15, wherein positioning the neuromodulation positioning patch on the subject's skin comprises adhering an applied layer of the neuromodulation positioning patch to the subject the skin of the person.

21. A neuromodulation positioning patch, comprising:

a conformable substrate including an opening extending through the conformable substrate;

an adhesive disposed on the application surface of the conformable substrate;

a resilient frame coupled to the base around a perimeter of the opening and protruding from a top surface of the conformable base, the resilient frame including one or more mating features; and

At least one docking piece for an ultrasound imaging probe, the at least one docking piece configured to removably mate with the resilient frame via one or more complementary mating features and the one or more mating features , wherein the abutment member forms a shaped channel terminating in a second opening, wherein the second opening is located within the first opening when the abutment member is engaged with the elastic frame.